Prostacyclins in PAH: Selecting Among the Agents

Charles Burger, MD: Prostaglandin had been involved in the pathophysiology of pulmonary arterial hypertension, specifically prostacyclin or prostaglandin I2. It’s a very potent vasodilator. It also is what we call an anti-proliferative agent, where it keeps the cells that line the pulmonary arterials and the cells in the walls of the pulmonary arterials under control, so that they don’t act in a way that narrows the lumen and increases pulmonary vascular resistance. The first drug actually approved for pulmonary arterial hypertension was an infusion prostacyclin called epoprostenol, and that’s really the only agent in which we have confirmed survival advantage. Because, there was no other treatment to compare it to when the original study was done. Subsequent therapies don’t have that advantage, because it wasn’t ethical to have a placebo-controlled arm.

Even in today’s expert guidelines for patients with severe class IV disease, moving to infusion prostanoids—which include epoprostenol and treprostinil—are the recommended treatment intervention. For patients with less severe disease, there’s an option to use other therapies. And, over time, the ability to deliver the prostanoids, the prostacyclin medications, have evolved from infusion to inhaled options and now oral preparations. So, in that one category of medications that target the prostaglandin pathway, we have oral, inhaled, and infusion options. It’s getting very complex in terms of the decision making about which of these to choose in which patient. And the science just isn’t there quite yet to make firm recommendations.

One should appreciate, however, that if you are on infusion therapy, that clearly is the one that has the documented improvement in survival. Using it in class IV disease is very appropriate. Second, you have zero order kinetics, so there’s a constant level in the bloodstream, and, therefore, treatment effect on the pulmonary circulation as opposed to if you’re delivering it by inhaled or oral where you have peaks and valleys of the medication. And you may not have coverage during nighttime, for example, depending on which of these you choose. So, it’s unknown as to whether inhaled and oral would ultimately be equivalent to an infusion prostanoid. There’s no information that says yes or no. I think the majority of the pulmonary arterial hypertension experts at this point would err on the side of the infusion therapy in a severe patient, and use inhaled or oral in a more moderately ill patient, perhaps in combination with the other classes of medications.

The infusion prostanoids are delivered by one of two routes. One option is to have an indwelling central venous catheter, so it’s delivered intravenously, connected to an infusion pump where the drug is prepared and installed in the pump, and run at a certain dosing rate. A second option is subcutaneous infusion. That applies to treprostinil, and the drug is 100% bioavailable when infused subcutaneously, again, connected to a line and an infusion pump with a dose that’s prepared and run at a particular dosing rate. The intravenous route has, of course, the indwelling line which runs some infection rate, albeit low. And if the line gets infected, obviously the chances of it progressing to a bacteremia or a systemic infection is a very real situation that needs to be monitored by the patient and the clinician. Because, that can be life-threatening if not detected early and treated appropriately.

The subcutaneous infusion does not have the risk of what we call line-related bacteremia, or line-related sepsis, that the intravenous infusion does. But, it does create a fair amount in the way of inflammation and pain at the infusion site. There’s particular and specific ways of managing that, that every patient who delivers the drug subcutaneously will have something in the way of a side effect at the infusion site, even if it’s just a modest amount of redness or swelling. But, that can range all the way to serious pain or even an abscess underneath the skin. So, there’s specific complications of these infusion medications that probably warrant, in almost all cases, the patient to be managed in an accredited pulmonary hypertension center where you have expert clinicians. And, more importantly, coordinators who are available on the phone to be able to respond to the patient when they call, and if they have an indwelling catheter and they’re having a fever, to direct them to the physician’s office for evaluation. Or if they’re infusing it subcutaneously and they're having inflammation or signs of infections that require early evaluation or intervention, then that’s done by an expert who has experience in managing these problems rather than in a general medical setting.

If you’re comparing infusion prostanoid therapy to the inhaled preparations, there are several important differences. With the infusion therapies, you have a constant dose that’s being provided systemically, to which the pulmonary arterial circulation and the right heart is exposed. You have a high degree of confidence that the dose that you’re providing, either intravenously or subcutaneously, is absorbed and is meeting your target blood level for action on the disease state. Secondly, it’s zero order kinetics, so there are no peaks and troughs of the medication. The exposure to the medication doesn’t vary whether you’re awake and taking the medication as it would with an inhaled preparation. It’s 24 hours of the same dose, same exposure.

With the inhaled preparations, of course, it requires a delivery system. And the medication is prepared and put in the delivery system, typically a proprietary delivery system or nebulizer in some cases. The medication is then delivered to the respiratory tract, some of which has to be hitting the oral pharynx, or the upper GI tract, or the larger airways, and perhaps not getting into the lower airways where the drug is active. It’s not clear how much might be absorbed systemically versus active locally in the pulmonary arterial circulation. There are peaks and troughs, so you have a high peak level right after you’ve administered it and then the drug is metabolized. And then, there’s no coverage during nighttime, because you aren’t delivering the drug while the patient is asleep. So, there’s a gap where the trough level of the medication is persistent beyond what you would anticipate would be the best for the patient in terms of therapeutic exposure. And then, you have issues potentially of irritating the respiratory tract, causing cough and wheezing that could also affect how much of the drug you’re delivering into the system.

Lastly, the infusion prostanoids really do not have a ceiling on dose. So, if a patient isn’t doing as well as anticipated, you can increase the infusion level of the medication really without a whole lot of concern about having some maximum dose beyond which you cannot prescribe the medication with some rare exceptions. The inhaled preparations of prostanoids have ceilings on the maximum amount of drug you can deliver, which is limited by the preparation of the drug and the delivery system.